Reduced creatine-stimulated respiration in doxorubicin challenged mitochondria: Particular sensitivity of the heart

University of Zurich, Zürich, Zurich, Switzerland
Biochimica et Biophysica Acta (Impact Factor: 4.66). 12/2007; 1767(11):1276-84. DOI: 10.1016/j.bbabio.2007.08.006
Source: PubMed


Doxorubicin (DXR) belongs to the most efficient anticancer drugs. However, its use is limited by a risk of cardiotoxicity, which is not completely understood. Recently, we have shown that DXR impairs essential properties of purified mitochondrial creatine kinase (MtCK), with cardiac isoenzyme (sMtCK) being particularly sensitive. In this study we assessed the effects of DXR on respiration of isolated structurally and functionally intact heart mitochondria, containing sMtCK, in the presence and absence of externally added creatine (Cr), and compared these effects with the response of brain mitochondria expressing uMtCK, the ubiquitous, non-muscle MtCK isoenzyme. DXR impaired respiration of isolated heart mitochondria already after short-term exposure (minutes), affecting both ADP- and Cr-stimulated respiration. During a first short time span (minutes to 1 h), detachment of MtCK from membranes occurred, while a decrease of MtCK activity related to oxidative damage was only observed after longer exposure (several hours). The early inhibition of Cr-stimulated respiration, in addition to impairment of components of the respiratory chain involves a partial disturbance of functional coupling between MtCK and ANT, likely due to interaction of DXR with cardiolipin leading to competitive inhibition of MtCK/membrane binding. The relevance of these findings for the regulation of mitochondrial energy production in the heart, as well as the obvious differences of DXR action in the heart as compared to brain tissue, is discussed.

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Available from: Uwe Schlattner
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    • "Cardiolipin is a major phospholipid component of the inner mitochondrial membrane and is required for the activity of respiratory chain. It is rich in polyunsaturated fatty acids and is particularly susceptible to peroxidative injury [23]; furthermore , evidence has been reported showing a strong affinity of doxorubicin for cardiolipin [24]. The drug-phospholipid complex formation leads to an inhibition of mitochondrial enzymes involved in oxidative phosphorylation. "
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    • "Second, we used a classical hemolysis assay with red blood cells (RBC) to demonstrate that PCr protects RBC from noxious insults by doxorubicin (Fig. 6A), hypoosmotic stress (Fig. 6B) and saponin (Fig. 6C). Hemolysis induced by doxorubicin can serve as a model of membrane damage related to oxidative stress [60], [61]. Supraclinical doxorubicin concentration of 300 µM induced hemolysis over a 5 h observation period. "
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    • "These discrepancies could be due to the experimental design or protocol used in each study and/or tissuespecific differences. Indeed, Tokarska-Schlattner and colleagues [28] evaluated the in vitro effect of DOX on heart and brain mitochondria and the authors observed that both types of mitochondria are affected by DOX. However, the results concerning brain mitochondria probably do not occur in vivo because DOX does not cross the blood–brain barrier [12]. "
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